Synapses are specialized cell adhesions that are the fundamental functional units of the nervous system, and they are generated during development with amazing precision and fidelity. During synaptogenesis, synapses form, mature, and stabilize and are also eliminated by a process that requires intimate communication between pre- and postsynaptic partners. In addition, there may be environmental determinants that help to control the timing, location, and number of synapses.
Synapses occur between neuron and neuron and, in the periphery, between neuron and effector cell, e.g. muscle. Functional contact between two neurons may occur between axon and cell body, axon and dendrite, cell body and cell body, or dendrite and dendrite. It is this functional contact that allows neurotransmission. Many neurologic and psychiatric diseases are caused by pathologic overactivity or underactivity of neurotransmission; and many drugs can modify neurotransmission, for examples hallucinogens and antipsychotic drugs.
During recent years, a great deal of effort has been made by investigators to characterize the function of synaptic proteins, which include synaptotagmin, syntexin, synaptophysin, synaptobrevin, and the synapsins. These proteins are involved in specific aspects of synaptic function, e.g. synaptic vesicle recycling or docking, and in the organization of axonogenesis, differentiation of presynaptic terminals, and in the formation and maintenance of synaptic connections.
Only by establishing synaptic connections can nerve cells organize into networks and acquire information processing capability such as learning and memory. Synapses are progressively reduced in number during normal aging, and are severely disrupted during neurodegenerative diseases. Therefore, finding molecules capable of creating and/or maintaining synaptic connections is an important step in the treatment of neurodegenerative diseases.
Astrocytes are the most abundant cell type in the brain, which ensheathe synapses throughout the central nervous system (CNS). They have been traditionally viewed as synaptic support cells, clearing ions and neurotransmitters from the synaptic cleft. Accumulating evidence has shown that astrocytes play an active role in the formation and function of synapses (see, for example, Ullian et al. (2004) Glia 47(3): 209-16; Ullian et al. (2004). Mol Cell Neurosci 25(2): 241-51; Christopherson et al. (2005). Cell 120(3): 421-33; Elmariah et al. (2005). J Neurosci 25(14): 3638-50).
It has been particularly difficult to study the role of glia in synaptogenesis in vitro because most CNS neuronal cultures contain glia, which are crucial for neuronal survival. For example, see culture conditions in Meyer-Franke et al. (1995) Neuron 15(4): 805-19. The modulation of synapse formation is of great interest for the treatment of a variety of nervous system disorders. To date, few soluble molecules have been identified that are sufficient to induce or increase the number of CNS synapses. Also of interest are soluble molecules capable of negatively modulating the formation of CNS synapses.